APPLICATION ID: 1 R56 MH113894-01A1 PI NAME: Cho, Jun-Hyeong PROJECT SUMMARY/ABSTRACT In order to survive, animals develop fear responses to dangerous situations and have evolved neural mechanisms to use an emotionally neutral cue as a conditioned stimulus (CS) to predict an aversive event. For adaptive fear responses, the brain must learn to discriminate between different sensory cues and associate only relevant stimuli with aversive events. Dysregulation of this process leads to maladaptive fear. A fundamental gap in understanding the mechanism underlying fear memory specificity limits research on fear-related disorders. The overall objective in this application is to determine the synaptic plasticity mechanism by which the brain encodes discriminative fear memory for a specific auditory cue in the auditory cortical/thalamic?amygdala path- ways. The central hypothesis is that fear memory for an auditory cue is encoded by selective long-term potentiation (LTP) in neural pathways, which convey specific auditory CS information to the amygdala, and such auditory input-specific LTP underlies fear memory specificity. Guided by preliminary data, this hypothesis will be tested by pursuing two specific aims: (1) Determine how selectively LTP is induced in the auditory CS pathways to the amygdala in discriminative auditory fear conditioning, and (2) Determine the role of auditory input-specific LTP in fear memory specificity. Under the first aim, a combined approach of behavioral labeling and electrophysiological recordings, will be used to analyze synaptic changes in auditory pathways conveying specific auditory information to the amygdala after discriminative auditory fear conditioning. Under the second aim, optogenetic stimulations of behaviorally-labeled auditory pathways to the amygdala will be used to erase specific fear memory for the auditory CS by reversing synaptic changes induced by fear learning. The proposed research is significant because it is expected to expand our understanding of how associative fear memory for a relevant sensory cue is encoded in the brain. Ultimately, such knowledge has the potential to inform the development of novel therapeutics to attenuate pathological fear.